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Background  Potential peripheral sources of deep pain can require invasive evocative tests for their assessment. Here we perform research whose ultimate goal is development of a non-invasive evocative test for deep painful tissue.    Methods  We used a rat model of inflammation to show that intense focused ultrasound (iFU) differentially stimulates inflamed versus control tissue and can identify allodynia. To do so we applied iFU to inflamed and normal tissue below the skin of rats’ hind paws and measured the amount of ultrasound necessary to induce paw withdrawal.    Results  iFU of sufficient strength (spatial and temporal average intensities ranged from 100–350 W/cm 2 ) caused the rat to withdraw its inflamed paw, while the same iFU applied to the contralateral paw failed to induce withdrawal, with sensitivity and specificity generally greater than 90%. iFU stimulation of normal tissue required twice the amount of ultrasound to generate a withdrawal than did inflamed tissue, thereby assessing allodynia. Finally, we verified in a preliminary way the safety of iFU stimulation with acute histological studies coupled with mathematical simulations.    Conclusions  Given that there exist systems to guide iFU deep to the skin, image-guided iFU may one day allow assessment of patient’s deep, peripheral pain generators.

Intense focused ultrasound stimulation can safely stimulate inflamed subcutaneous tissue and assess allodynia